Interferon induction and prostaglandin synthetase inhibition in the in vitro and in vivo manipulation of immune response expression in an animal model of bladder cancer

Since prostaglandin E₂ (PGE₂) and interferon (IF) production during lymphocyte/macrophage-tumor cell interactions have been suggested to influence immune response expression during tumor development, we thought it of interest to manipulate the production of these substances in vitro and in vivo to see if this altered effector cell cytotoxicity in models of implantable and carcinogen-induced bladder tumors. Baseline levels of lymphocyte cytotoxicity were in general depressed in tumor-bearing animals compared to age-matched controls in the carcinogen-induced model. Addition of peritoneal macrophages to these preparations neither increased nor decreased these levels. Moreover, addition of indomethacin to these assays, or inoculation of indomethacin in vivo did not consistently alter levels of cytotoxicity from base-line. In contrast, interferon added in vitro increased splenic lymphocyte cytotoxicity in both control and tumor-bearing animals, and intraperitoneal inoculation of poly I:C, an inducer of interferon, consistently enhanced splenic lymphocyte cytotoxicity from both animal groups. The implantable tumor model was somewhat different in that indomethacin in vitro was found in selected conditions to enhance cytotoxicity by splenic lymphocytes when peritoneal macrophages were added to lymphocyte suspensions. A similar effect on splenic lymphocyte or peritoneal macrophage activity alone, however, was not observed. In vivo inoculation of indomethacin also did not appear to alter lymphocyte cytotoxicity. In this model, in vitro interferon again enhanced lymphocyte cytotoxicity while inoculation of poly I:C in vivo consistently enhanced lymphocyte activity. Surprisingly, inoculation of both indomethacin and poly I:C in vivo led to less enhancement of cytotoxicity. Taken together, it appeared that the immune response in both a carcinogen-induced and a transplantable tumor model could be enhanced by interferon induction, that attempts to regulate prostaglandin E₂ production in vivo or in vitro did not generally enhance cytotoxicity unless macrophages were present during cytotoxicity testing, and that manipulation of both substances led to less enhancement than was seen with interferon modulation alone.